JP2003518006A - Contraceptive compositions containing cyclic carbamates and amide derivatives - Google Patents

Abstract

(57) [Summary] The invention provides a compound of the general structure (I) wherein A and B are independent substituents selected from S, CH or N; when A is S, B is CH or N; A is CH or N when A is S; and A and B cannot both be CH; and when A and B are both equal to N, one N is optionally a C ₁ -C ₆ alkyl group R ₁ and R ₂ may be H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C ₂ -C _6. alkenyl, C ₂ -C ₆ alkynyl, substituted C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR ^A, or NR separate location selected from the group consisting of ^B COR ^a Is a group; or, R ₁ and R ₂ are 3-8 membered spirocyclic alkyl substituted optionally fused, to form an alkenyl or heterocyclic ring, heterocyclic ring, A substituted indoline derivative compound which is a progesterone receptor antagonist having a heteroatom selected from the group consisting of O, S and N], or a pharmaceutically useful salt thereof, using progestin, estrogen or both. The present invention relates to a cyclic combination therapy and a prescription utilized in combination with the above. These treatments may be used for contraception or for secondary amenorrhea, dysfunction bleeding, uterine leiomyoma, endometriosis; polycystic ovary syndrome, endometrial, ovarian, breast, colon, prostate cancer It may be used to treat and / or prevent tumors and adenocarcinomas, or to minimize side effects or periodic menstrual bleeding. Further uses of the invention include stimulating food intake.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to formulations for administering compounds that are antagonists of progesterone receptors in combination with progestins, estrogens, or both.

BACKGROUND intracellular receptors invention (IR) form a single class of genetic regulators structurally related known as "ligand dependent transcription factors" (R.M.Evans
, Science, 240 , 889, 1988). The steroid receptor family is a subset of the IR family that includes the progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) Is.

The natural hormone, or ligand, for PR is the steroid progesterone, but synthetic compounds have been made, such as medroxyprogesterone acetate or levonorgestrel, which also serve as ligands. When the ligand is present in the fluid surrounding the cell, it passes through the membrane via passive diffusion and binds IR to form the receptor / ligand complex. This complex then translocates to the nucleus of the cell where it binds to specific genes present in the cell's DNA. When bound to a specific DNA sequence, the complex regulates the production of mRNA and protein encoded by that gene.

Compounds that bind IR and mimic the action of natural hormones are called agonists, while compounds that suppress the effects of hormones are antagonists. PR agonists (natural and synthetic) are known to play important roles in women's health.
PR agonists are used in birth control formulations, typically in the presence of ER agonists. ER agonists are used to treat menopausal symptoms, but are implicated in their proliferative effects on the uterus (in women who have not undergone hysterectomy) which increase the risk of uterine cancer. Co-administration of PR agonists reduces or eliminates that risk. PR antagonists can also be used in contraception. In this regard, they are alone (Ulmann, et al, Ann.N.Y.Acad.Sci. , 26 1, 248,1995), in combination with a PR agonist (Kekkonen, et
al, Fertility and Sterility, 60 , 610, 1
993), or in combination with a partial ER antagonist such as tamoxifen (W
O96 / 19997, published July 4, 1996).

[0005]   In addition, PR antagonists are hormone-dependent breast cancer (Horwitz, et al, Horm. Cancer , 283, pub: Birkhaeuser, Boost
on, Mass. , Ed. Vedeckis) and treatment of uterine and ovarian cancer
It is also useful for medical treatment. PR antagonists can also be used to treat non-malignant chronic conditions such as fibroids.
Tumor (Murphy, et al,J. Clin. Endo. Metab. , 76 , 513, 1993) and endometriosis (Kettel, et al,Fert ility and Sterility, 56 , 402, 1991)
Would be useful for.

PR antagonists may also be useful in hormone replacement therapy for post-menopausal patients in combination with partial ER antagonists such as tamoxifen (US Pat. No. 5,719,136). PR antagonists, such as mifepristone, have also been shown to have bone sparing effects in rodents and may be useful, for example, in the treatment of menopausal osteoporosis (Barengolts, et a.
1, Bone, 17 , 21 , 21 , 1995). PR antagonists, such as mifepristone and onapristone, have been shown to be effective in models of hormone-dependent prostate cancer and may suggest their utility in treating this condition in men. I don't know (Michn
a, et al, Ann. N. Y. Acad. Sci. 761 , 224, 199
5).

[0007] Jones et al. (US Pat. No. 5,688,810) describe a PR antagonist dihydroquinoline 1 .

[0008]

[Chemical 9]

[0009] Jones et al., Enol ether 2 as a PR ligand (US Pat.
No. 693,646).

[0010]

[Chemical 10]

[0011] Jones et al., Compound 3 as a PR ligand (US Pat. No. 5,696,1)
No. 27) is described.

[0012]

[Chemical 11]

Zhi et al . Describe lactones 4 , 5 and 6 as PR antagonists ( J. Med. Chem., 41 , 291, 1998).

[0014]

[Chemical 12]

Zhi et al . Describe ether 7 as a PR antagonist ( J. Med . Chem ., 41 , 291, 1998).

[0016]

[Chemical 13]

[0017] Combs et al . Discloses amide 8 as a ligand for PR ( J. Med. Chem., 38 , 4880, 1995).

[0018]

[Chemical 14]

Perlman et al. Have described vitamin D homolog 9 as a PR ligand ( Tet . Letters, 35 , 2295, 1994).

[0020]

[Chemical 15]

Hamann et al. Describe a PR antagonist 10 ( Ann . NY Aca d. Sci. 761 , 383, 1995).

[0022]

[Chemical 16]

Chen et al. Describe a PR antagonist 11 (Chen, et al, PO.
I-37,16 ^th Int. Cong. Het. Chem. Montana, 1
997).

[0024]

[Chemical 17]

[0025] Kurihari et al. Describe PR ligand 12 ( J. Antibiotics, 50 , 360, 1997).

[0026]

[Chemical 18]

US Pat. No. 5,521,166 (Grubb) discloses a cyclophasic hormone comprising an antiprogestin and a progestin when the progestin is administered in the alternating presence and absence of the antiprogestin. Teaching prescription. The disclosed formulation is also a breakthrough.
gh) Consider using estrogen for a period of 2-4 days to prevent bleeding.

DESCRIPTION OF THE INVENTION The present invention provides combination therapies and dosing regimens that utilize an anti-pregnant drug in combination with one or more progestational drugs. The invention further provides therapeutic methods and dosage regimens that further utilize estrogens, such as ethinyl estradiol, in combination with these anti-progestins and progestins.

These formulations and combinations may be used to induce contraception or secondary amenorrhea, dysfunctional hemorrhage, uterine leiomyoma, endometriosis; polycystic ovary syndrome, endometrium,
It may be administered to mammals for the treatment and / or prevention of ovarian, breast, colon and prostate carcinomas and adenocarcinomas. Further uses of the invention include stimulation of food intake. The use herein for the treatment and / or prophylaxis of the above-mentioned conditions or disorders is intended for the continuous administration or intermittent administration of the present invention to enable the minimization of effective doses or the reduction of side effects or periodic menstrual bleeding. Including a break.

Uses of the invention for contraception include the administration of antiprogestins in combination with estrogen or progestin or both, preferably orally, to women of pregnancy age. These dosage regimens are preferably progestin,
With the final part of the cycle, including no estrogen or antiprogestin,
It is carried out for 28 consecutive days.

The progestins of these combinations may be administered alone or in combination with estrogens for the first 14-24 days of the cycle, the progestins being at about 35 μg to about 150 μg levonorgestrel per day in pre-gestational activity. , Preferably in activity at a dose range equal to about 35 μg to about 100 μg of levonorgestrel per day. Then the anti-progestin
It may be administered alone or in combination with estrogen, starting on the day of any cycle between days 14 and 24, for a period of 1 to 11 days. The anti-progestin in these combinations may be administered at a dose of about 2 μg to about 50 μg per day and the estrogen may be administered at a dose of about 10 μg to about 35 μg per day. For oral administration, a package or kit containing 28 tablets will contain placebo tablets in the days that the anti-progestin or progestin or estrogen is not administered.

In a preferred embodiment of the invention, the progestin of the invention comprises the first 1 of the 28-day cycle.
It may be administered alone or in combination with estrogen for 8 to 21 days, followed by antiprogestin for 1 to 7 days, alone or in combination with estrogen.

The estrogen used in the combinations and formulations of the present invention is preferably ethinyl estradiol.

The progestational agents useful according to the present invention include, but are not limited to, levonorgestrel, norgestrel, desogestrel, 3-keto desogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, Includes trimegeston, dienogest, drospirenone, nomegestrol or (17-deacetyl) norgestimate. Suitable progestins for use in the combinations of the invention are levonorgestrel, gestodene and trimegeston.

An example of an oral dosage regimen of the invention over a 28-day cycle includes administration of a progestational drug alone for the first 21 days in a daily dose equal to about 35 to about 100 μg levonorgestrel in progestational activity. . The anti-progestin compound of the invention is then administered in a daily dose of about 2-50 mg from day 22 to day 24,
Subsequent days 25-28 may be given no treatment or placebo. Optimally, the daily doses of each relevant active ingredient will be incorporated into a combined single daily dose unit and 28 daily units combined per 28 day cycle.

In other formulations, the pre-gestational agent is a daily dose in which the pre-gestational agent is at a daily dose equal to about 35 to about 150 μg levonorgestrel in pre-pregnancy activity, preferably about 35 to about 100 μg levonorgestrel in activity. It may be co-administered with an estrogen, eg ethinyl estradiol, in the range of about 10 to about 35 μg for the first 21 days. This is the antiprogestin administered at a daily dose of about 2 to 50 mg from day 22 to day 24, as described above, followed by 2
No administration or placebo administration may continue during days 5-28.

Yet another formulation within the scope of the present invention is a pre-pregnant drug, ie a pre-pregnant drug, preferably levovo, which is administered in a daily dose equal to about 35 to about 100 μg of levonorgestrel in pre-pregnant activity. Concomitant administration of norgestrel and an estrogen such as ethinyl estradiol in a daily dose range of about 10 to about 35 μg from day 1 to day 21 may be included. This is 22-24
On day 1, antiprogestin (2-50 mg / day) and daily dose of about 10 to about 35
Following the co-administration of an estrogen, eg ethinyl estradiol, in μg. From day 25 to day 28, the formulation may be naive or followed by placebo.

The invention also provides a kit or package of formulations designed for use in the formulations described herein. These kits are preferably designed for daily oral administration over a 28-day cycle, preferably once daily, and a single oral or oral formulation taken on each day of the 28-day cycle. Are configured to specify a combination of. Preferably, each kit will contain oral tablets to be taken on a particular day, preferably one oral tablet will each contain the combined indicated daily dose.

According to the above formulation, one 28-day kit comprises: a) Levonorgestrel in pregestational activity equal to about 35 to about 150 μg, preferably about 35 to about 100 μg levonorgestrel in pregestational activity.
An anti-progestin compound of the invention, wherein the daily dose unit of the progestational agent is 14-21 days for 1 to 21 days; b) each daily dose unit contains an anti-progestin compound at a daily dose of about 2 to 50 mg. Oral and pharmaceutically acceptable placebo for the remaining days of the cycle in which antiprogestin, progestin or estrogen is not administered, optionally in a second dosage unit of 1 to 11 days of the second phase of; The third phase of: may be included.

Preferred embodiments of this kit include: a) Levonorgestrel at a progestational activity equal to about 35 to about 150 μg of levonorgestrel, preferably about 35 to about 100 μg of levonorgestrel at a progestational activity.
21 daily dose units of pre-gestational drug equal to 21 days of the first phase; b) 22 of the anti-progestin compounds of the present invention wherein each daily dose unit contains the anti-progestin compound at a daily dose of about 2 to 50 mg. Daily phase of 3 daily dose units between days -24; and c) optionally daily unit 4 of orally and pharmaceutically acceptable placebo for days 25-28, respectively. Phase 3 for the day: may be included.

Other 28 day cycle packaging formulations or kits of the invention include: a) a pregestational activity equal to about 35 to about 150 μg of levonorgestrel in progestational activity, preferably about 35 to about 100 μg of levonorgestrel in activity. Phase 1 of a daily dosage unit 18-21 days of an active agent and ethinyl estradiol in the daily dose range of about 10 to about 35 μg as estrogen; b) an antiprogestin of the invention at a daily dose of about 2 to 50 mg. Daily dose unit of 1 to 7 days of the second phase; and c) optionally for each of the remaining 0 to 9 days in a 28 day cycle in which the pregestational drug, estrogen or antiprogestin is not administered. And pharmaceutically acceptable placebos:

Preferred embodiments of the above kit include: a) a pre-pregnant drug in estrogen equal to about 35 to about 150 μg levonorgestrel in pre-pregnancy activity, preferably about 35 to about 100 μg levonorgestrel in activity. 21 days of a daily dose unit of 21 days of the first phase of ethinyl estradiol in a daily dose range of about 10 to about 35 μg; and b) 22 to 24 of antiprogestins administered in a daily dose of about 2 to 50 mg.
Daily dose unit for day 3 Phase 2 for 3 days; and c) optionally a daily dose unit 4 of orally and pharmaceutically acceptable placebo for each of days 25-28. Phase 3 for the day: may be included.

A further 28-day packaged formulation or kit of the invention comprises: a) a daily dose equal to about 35 to about 150 μg levonorgestrel in progestational activity, preferably about 35 to about 100 μg levonorgestrel in activity. The pre-pregnant drug of the present invention, and the daily dose range of about 10 to about 35μ.
daily dose unit 18-2 each containing ethinyl estradiol in g
1 day of the first phase; b) 1 to 7 daily dosage units, each daily dosage unit containing the antiprogestin of the invention at a concentration of 2 to 50 mg and ethinyl estradiol at a concentration of about 10 to about 35 μg. 2); and c) optionally an orally and pharmaceutically acceptable placebo for each of the remaining 0-9 days in the 28-day cycle in which the progestational drug, estrogen or antiprogestin is not administered: including.

Preferred embodiments of the packaging or kit just described include: a) Pregnancy of the invention in a daily dose equal to about 35 to about 150 μg levonorgestrel, preferably about 35 to about 100 μg levonorgestrel in pre-gestational activity. Phase 1 of 21 daily dosage units, each containing a prodrug, and ethinyl estradiol in a daily dose range of about 10 to about 35 μg; b) an antiprogestin of the invention at a concentration of 2-50 mg, and a concentration. 22 to 22 each dose unit containing ethinyl estradiol at about 10 to about 35 μg.
Daily dose unit for day 24, 3 days of second phase; and c) optionally, daily unit of orally and pharmaceutically acceptable placebo for each of days 25-28. Day 3 Phase 3: Including.

In each of the formulations and kits just described, it is preferred that the daily dose of each pharmaceutically active ingredient of the formulation remains fixed in each particular phase in which it is administered. It is also understood that the daily dosage units must be administered in the order listed, in the order of phase 1 followed by phases 2 and 3. It is also preferred that the kit contains said placebo for the last days of the cycle in order to simplify the complexity associated with each formulation. It is further preferred that each package or kit comprises a pharmaceutically acceptable package with an indicator for each day of the 28-day cycle, such as a labeled blister package or dial dispenser package known in the art. Is.

In the present disclosure, the terms antiprogestational drug, antiprogestin and progesterone receptor antagonist are understood to be synonymous. Similarly, progestins, progestational agents and progesterone receptor agonists are understood to refer to compounds of the same activity.

These dosage regimens may be adjusted to provide the optimal therapeutic response.
For example, several divided doses of each component may be administered daily, or the dose may be proportionally increased or reduced as indicated by the exigencies of the therapeutic situation. In the description herein, references to daily dosage units may also include divided units administered over the daily course of the cycle under consideration.

Compounds of the present invention that can be used as anti-preterm agents in the kits, methods and formulations herein include compounds of Formula I:

[0049]

[Chemical 19]

Wherein A and B are independent substituents selected from S, CH or N, provided that when A is S B is CH or N; B is S Where A is CH or N; and A and B cannot both be CH; and A and B
Are both equal to N, one N may be optionally substituted by a C ₁ -C ₆ alkyl group; R ₁ and R ₂ are H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, substituted C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, Is an independent substituent selected from the group of aryl, substituted aryl, heterocycle, substituted heterocycle, COR ^A or NR ^B COR ^A ; or R ¹ and R ² are fused: a) optionally Substituted 3-8 membered spirocyclic alkyl ring, preferably 3
~ 6 membered spiro cyclic alkyl ring; or b) optionally substituted 3 to 8 membered spiro cyclic alkenyl ring, preferably 3 to 6 membered spiro cyclic alkenyl ring; or c) O, S and Optionally substituted 3-8 membered spirocyclic ring containing 1-3 heteroatoms selected from N, preferably containing 1-3 heteroatoms
To a 6-membered spirocyclic ring; R ^A is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C _1-. C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ^B is H, be a C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl; R ³ is H, OH, NH _2, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₁ -C ₆ alkenyl, alkynyl or substituted alkynyl, or COR ^C; R ^C is , H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C _1-. It is a C ₃ aminoalkyl; R ⁴ is as follows Suyo substituents X, trisubstituted benzene ring containing the Y and Z:

[0051]

[Chemical 20]

Wherein X is halogen, CN, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ thioalkyl , Substituted C ₁ -C ₃ thioalkyl, C ₁ -C ₃ aminoalkyl, substituted C ₁ -C ₃ aminoalkyl, NO ₂ , C ₁ -C ₃ perfluoroalkyl, 5- or 6-membered containing 1-3 heteroatoms selected heterocyclic ring, COR ^D, from OCOR ^D, or NR ^E COR ^D; R ^D is, H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; ^RE is H, C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl Y and Z are H, Ha Gen, CN, NO _2, or C ₁ -C ₃ alkoxy, independently selected from C ₁ -C ₃ alkyl or C ₁ -C ₃ thioalkyl; or, R ⁴ is, O, S, SO, SO ₂ or Containing 1, 2 or 3 heteroatoms from the group comprising NR ⁵ and H, halogen, CN, NO ₂ and C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl , COR ^F or NR ^G CO
Is a 5 or 6 membered ring containing 1 or 2 independent substituents from the group comprising R ^F ; R ^F is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted Aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ^G is H, C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl; R ⁵ is H or C ₁ -C ₃ alkyl; W is O or a chemical bond], or a pharmaceutically acceptable salt thereof.

In preferred anti-pregnant compounds for use according to the invention, A and B are independent substituents S, CH or N, provided that when A is S, B is CH or N is N; and B is S, then A is CH or N; and A and B cannot both be CH; and when A and B are both equal to N, one N is optionally C ₁ -C ₆ alkyl group may be substituted by; R ¹ is, H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR ^A, or NR ^B COR ^A; R ² is, H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ Alkenyl,
Substituted C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ substituted alkynyl, C ₃
-C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, COR ^A or NR ^B COR ^A ; or R ₁ and R ₂ are fused. A) an optionally substituted 3-8 membered spirocyclic alkyl ring; or b) an optionally substituted 3-8 membered spirocyclic alkenyl ring; or c) a group of O, S and N. optionally containing one to three heteroatoms selected from the spirocyclic rings of 3 to 8 membered substituted; to form a; R ^a is, H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ^B is, H, C ₁ - C ₃ alkyl or substituted C ₁ - Is ₃ alkyl; R ³ is, H, OH, NH _2, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₁ -C ₆ alkenyl, alkynyl or substituted alkynyl Or COR ^C ; R ^C is H, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl, aryl, substituted aryl, C ₁ -C ₄ alkoxy, substituted C ₁ -C ₄ alkoxy, C _1-. C ₄ aminoalkyl or substituted C ₁ -C ₄ aminoalkyl; R ⁴ is a trisubstituted benzene ring containing substituents X, Y and Z as shown below:

[0054]

[Chemical 21]

Wherein X is halogen, CN, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ thioalkyl , A substituted C ₁ -C ₃ thioalkyl, a C ₁ -C ₃ aminoalkyl, a substituted C ₁ -C ₃ aminoalkyl, NO ₂ , a C ₁ -C ₃ perfluoroalkyl, a 5-membered complex containing 1 to 3 heteroatoms. ring, COR ^D, selected from OCOR ^D, or NR ^E COR ^D; R ^D is, H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy , C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ^E is H, C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl Y and Z are H, halogen, N, NO _2, C ₁ -C ₃ alkoxy, or is an independent substituent selected from C ₁ -C ₃ alkyl or C ₁ -C ₃ group comprising thioalkyl; or, R ⁴ is, O, S, SO , SO ₂ or NR ⁵ containing 1, 2 or 3 heteroatoms from the group and containing H, halogen, CN, NO ₂ and C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy. Is a 5- or 6-membered ring containing 1 or 2 independent substituents of; R ⁵ is H or C ₁ -C ₃ alkyl; W is O or a chemical bond: a compound of formula I, Alternatively, it is a pharmaceutically acceptable salt thereof.

Further preferred progesterone receptor antagonists are: A and B are independent substituents from the group comprising S, CH or N, provided that when A is S, B is CH or N. And when B is S, A is CH or N; and A and B cannot both be CH; R ¹ = R ² and C ₁ -C ₃ alkyl, substituted C _1- C ₃ alkyl, or R ₁
And R ₂ is selected from the group comprising spirocyclic alkyl constructed by condensing R ₂ to form a 3-6 membered spirocyclic ring; R ³ is H, OH, NH ₂ , C _1-. C ₆ alkyl, substituted C ₁ -C ₆ alkyl or CO
R ^C ; R ^C is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; R ⁴ is a disubstituted benzene ring containing substituents X and Y as shown below:

[0057]

[Chemical formula 22]

Wherein X is halogen, CN, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, NO ₂ , C _1-
C ₃ perfluoroalkyl, a 5 membered heterocyclic ring containing 1-3 heteroatoms,
Or selected from the group containing C ₁ -C ₃ thioalkyl; Y is selected from the group of H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl or C ₁ -C ₃ thioalkyl. Is a substituent at the 4'or 5'position; or R ⁴ is a structure shown below:

[0059]

[Chemical formula 23]

A five-membered ring having: U is O, S or NR ⁵ , R ⁵ is H or C ₁ -C ₃ alkyl or C ₁ -C ₄ CO ₂ alkyl; Is selected from halogen, CN, NO ₂ , C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy; Y ′ is H or C ₁ -C ₄ alkyl; or R ⁴ has the structure:

[0061]

[Chemical formula 24]

A six-membered ring having: X ¹ is N or CX ² ; X ² is halogen, CN or NO ₂ ; W is O or a chemical bond: a compound of formula I Or a pharmaceutically acceptable salt thereof.

The antiprogestational compounds of the present invention may contain asymmetric carbon atoms, and some of the compounds of the present invention may contain one or more asymmetric centers, thus Optical isomers and diastereomers may occur. Formulas I, II and II
Although shown in I regardless of stereochemistry, the present invention provides such optical isomers and diastereomers; and racemic and resolved enantiomerically pure R and S stereoisomers; and R And other mixtures of S stereoisomers, and their pharmaceutically acceptable salts.

The term “alkyl” is used herein to refer to both straight and branched chain saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. "Alkenyl" refers to carbon atoms 2 having at least one carbon-carbon double bond.
It is meant to include both straight and branched chain alkyl groups having 8 and preferably 2 to 6 carbon atoms; an "alkynyl" group is a carbon atom having at least one carbon-carbon triple bond, 2 carbon atoms. It is meant to include both straight and branched chain alkyl groups having from ˜8, preferably from 2 to 6 carbon atoms.

The terms “substituted alkyl”, “substituted alkenyl” and “substituted alkynyl” refer to halogen, CN, OH, NO ₂ , amino, aryl, heterocycle, substituted aryl, substituted heterocycle, alkoxy, aryloxy, substituted alkyl. It refers to just the aforementioned alkyl, alkenyl and alkynyl having one or more substituents from the group including oxy, alkylcarbonyl, alkylcarboxy, alkylamino, alkylthio. These substituents may be attached to any carbon of the alkyl, alkenyl or alkynyl groups provided the bond comprises a stable chemical moiety.

The term “aryl” refers to a single ring or at least one of a fused or bonded ring.
Used herein to refer to an aromatic system that may be multiple aromatic rings fused or bonded together to form a conjugated aromatic system. Aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl.

The term “substituted aryl” refers to halogen, CN, OH, NO ₂ , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino or alkylthio. Refers to aryl as defined immediately above with one or more substituents from the group comprising.

The term “heterocycle” is a stable, partially unsaturated or unsaturated and stable carbon atom and from 1 to 4 heteroatoms selected from the group comprising N, O and S atoms. Used herein to describe a 4-7 membered monocyclic or stable polycyclic heterocyclic ring. The N and S atoms may be oxidized. Heterocyclic rings also include any polycyclic ring in which any of the above heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom so long as the resulting structure is chemically stable. Such a heterocyclic group is
For example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl,
Includes thiamorpholinyl, thiamorpholinyl sulfoxide and isoquinolinyl.

The term “substituted heterocycle” includes halogen, CN, OH, NO ₂ , amino, alkyl,
Just as defined, having one or more substituents selected from the group comprising substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino or alkylthio. Are used herein to describe such heterocycles. The term "alkoxy" is used herein to refer to an OR group where R is alkyl or substituted alkyl. The term "aryloxy" is used herein to refer to an OR group where R is aryl or substituted aryl.
The term "alkylcarbonyl" refers to RC where R is alkyl or substituted alkyl.
Used herein to refer to the O group. The term "alkylcarboxy" is used herein to refer to a COOR group where R is alkyl or substituted alkyl. The term "aminoalkyl" refers to both secondary and tertiary amines, where the alkyl or substituted alkyl groups can be the same or different and the point of attachment is on the nitrogen atom. The term "thioalkyl" is used herein to refer to an SR group where R is alkyl or substituted alkyl. The term "halogen" means
It means Cl, Br, F or I element.

The anti-progestin compounds of the invention can be prepared according to the schemes illustrated below: Cyclocarbamate Derivatives Method for Preparing Thiophenecyclocarbamate Derivatives A. A method of synthesizing the thiophene cyclocarbamate compound shown in Scheme 1 is described below:

[0071]

[Chemical 25]

Thus, the aminothiophene ester 2 can be treated with the Gewald reaction (Compre
Hensive Heterocyclic Chemistry II. A
Review of the Literature 1982-1995. A
． R. Katrisky et al. Vol. 2 page 639),
It was prepared according to literature procedures requiring reaction of an appropriately substituted aromatic acetaldehyde with sulfur and methyl cyanoacetate in refluxing methanol (Scheme 1). Reaction of the 2-amino group with the appropriate chloroformate or carbonate gives the protected amine 3 . This is a solvent such as benzene,
Chloroformate or carbonate derivative in toluene, xylene, dichloromethane, tetrahydrofuran or pyridine, such as methyl chloroformate, ethyl chloroformate, allyl chloroformate, 2- (trimethylsilyl) ethyl chloroformate, or di-tert-butyl bicarbonate. It can be accomplished by reacting 2 and 2 . The reaction is carried out under an inert atmosphere (nitrogen or argon) from 0 ° C. to the reflux temperature of the solvent and may require the presence of a base such as 4-dimethylaminopyridine, triethylamine, pyridine or di-isopropylethylamine. Then, an organometallic reagent such as Grignard reagent, alkyl or alkyl of the protected amino compound 3 in an inert solvent (tetrahydrofuran or diethyl ether) under an inert atmosphere (nitrogen or argon) at a suitable temperature from 0 ° C. to the reflux temperature of the solvent. Treatment with an aryl-zinc reagent, an alkyl or aryl lithium reagent yields the tertiary alcohol 4 . Compound 4 is then brought to the basic state effective for ring closure to form cyclocarbamate derivative 5 . Suitable conditions may include treatment of 4 with a solvent such as potassium hydroxide in ethanol or a base such as potassium t-butoxide in a solvent such as tetrahydrofuran. The reaction can be carried out at 0 ° C. to the reflux temperature of the solvent under an inert atmosphere (nitrogen or argon).

[0073]

[Chemical formula 26]

Alternatively, the carbamate protecting group present in 4 may be removed under conditions suitable for its removal to give 6 (Scheme 2). Subsequent ring closure of 6 with a reagent such as phosgene, carbonyldiimidazole or dimethyl carbonate in a suitable solvent (tetrahydrofuran, dichloromethane, benzene, etc.) will also give formation of 5 .

[0075]

[Chemical 27]

Alternatively, compound 4 is dehydrated to produce isopropene derivative 7 (Scheme 3). Suitable conditions for dehydration are acetic anhydride, methanesulfonyl chloride, in a solvent such as pyridine, tetrahydrofuran, dichloromethane or benzene,
Use of reagents such as p-toluenesulfonyl chloride or trifluoromethanesulfonyl chloride or anhydride. The reaction is carried out under an inert atmosphere (nitrogen or argon) from 0 ° C. to the reflux temperature of the solvent and may require the presence of a base such as 4-dimethylaminopyridine, triethylamine, pyridine or di-isopropylethylamine. The 7 is then exposed to an acidic state to undergo a ring closure to produce 5 . Suitable conditions would be the use of an acid such as p-toluenesulfonic acid, methanesulfonic acid or camphorsulfonic acid in a solvent such as dichloromethane, benzene, toluene or tetrahydrofuran. The reaction can be carried out at 0 ° C. to the reflux temperature of the solvent under an inert atmosphere (nitrogen or argon).

[0077]

[Chemical 28]

[0078]   5An alternative route to is shown in Scheme 4. Then, 0 ° C to the reflux temperature of the solvent
Under an inert atmosphere (nitrogen or argon) at an appropriate temperature of
Lahydrofuran, diethyl ether) in organometallic reagents such as Grinard
Reagents, alkyl or aryl zinc reagents, alkyl or aryl lithium
Already described compounds with reagents8(M. Sugiyama, T. Saka
moto, K .; Tabata, K .; Endo, K .; Ito, M .; Kobayas
hi, H.H. Fukiumi,Chem. Pharm. Bull. , 37(8):
2091 (1989)), tertiary alcohol9Cause Then compound
object9Is brought to an effective basic state for ring closure and is a cyclocarbamate derivative1 0 To generate. Suitable conditions are potassium hydroxide in a solvent such as ethanol or
In a solvent, for example a base such as potassium t-butoxide in tetrahydrofuran 10 Including processing of. The reaction is carried out at an inert atmosphere (nitrogen or
Can be carried out under argon). Compound10Is the brominated derivative11Was converted to
May be. Suitable conditions also include solvents such as dichloromethane, tetrahydrofuran.
Specifically, it is a treatment with bromine or N-bromosuccinimide in acetic acid. reaction
Is an inert atmosphere in the presence of an additive such as silica gel at a temperature of 0 ° C to the reflux temperature of the solvent.
It can be carried out under (nitrogen or argon). Aryl or heteroaryl
With rhoic acid, boronic anhydride or trialkylstannane11Subsequent reaction of
The desired biaryl compound5To get The reaction is carried out with a palladium catalyst such as tet
Of lakis (triphenylphosphine) palladium (0) or palladium acetate
In the presence of an inert atmosphere (nitrogen or argon) at 0 ° C to the reflux temperature of the solvent,
Solvent such as acetone, ethanol, benzene, toluene or tetrahydro
Carried out in furan, and sodium carbonate, cesium fluoride or potassium carbonate
Additives such as lithium may be required.

[0079]

[Chemical 29]

Alternatively, 10 (Scheme 5) is treated at low temperature with a reagent such as an alkyllithium or lithium amide in an inert solvent, eg tetrahydrofuran, and then the boronic acid 1 under the action of trimethyl borate or triisopropyl. 2 (M = B (OH) ₂ ) or via reaction with trimethyltin chloride or bis (trimethyltin) chloride to stannane. Subsequently in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) or palladium acetate and may require additives such as sodium carbonate, cesium fluoride or potassium phosphate, bromide or iodide. Reaction of 12 with an aryl or heteroaryl would then lead to conversion to the desired thiophene cyclocarbamate 5 .

B. A method for synthesizing the thiophene cyclocarbamate compound shown in Scheme 6 is described below:

[0082]

[Chemical 30]

[0083]   Aminothiophene compound15(Scheme 6) is a manipulation of literature (Compreh
native Heterocyclic Chemistry II. AR
view of the Literature 1982-1995. A.
R. Katrisky et al. Vol. 2 page 639)
The procedure is based on the appropriately substituted aromatic methyl ketone.ThirteenTo
Treated with phosphorus oxychloride in N, N-dimethylformamide to give chlorocyanate.
No-olefin derivative14To generate. Contains sodium methoxide
Methyl mercaptoacetate in methanol14Reacts, important aminothiof
The encarboxylate starting material is produced. 2-amino group and suitable chloroformic acid
Amines protected by reaction with stellates or carbonates16To generate.
This is a solvent such as benzene, toluene, xylene, dichloromethane, tetra
Induction of chloroformate or carbonate in hydrofuran or pyridine
Conductors such as methyl chloroformate, ethyl chloroformate, allyl chloroformate, chloro
2- (trimethylsilyl) ethyl formate or di-tert-butyl bicarbonate1 5 Can be accomplished by reacting. The reaction is inactive at 0 ° C to the reflux temperature of the solvent.
Performed under a neutral atmosphere (nitrogen or argon) and a base such as 4-dimme
Cylaminopyridine, triethylamine, pyridine or di-isopropyl ether
The presence of tylamine may be required. Then, a suitable temperature of 0 ° C to the reflux temperature of the solvent
Under an inert atmosphere (nitrogen or argon) at an inert solvent (tetrahydrofuran
, Diethyl ether), organometallic reagents such as Grinard's reagent, alkyne
Or aryl-zinc reagent, alkyl or aryl lithium reagent
Protected amino compounds16In the treatment of, tertiary alcohol17Cause Then compound
object17Is brought to an effective basic state for ring closure and is a cyclocarbamate derivative 18 To get Suitable conditions are potassium hydroxide or theta in a solvent such as ethanol.
With a base such as potassium t-butoxide in trahydrofuranFourIncluding processing
. The reaction is carried out at 0 ° C to the reflux temperature of the solvent under an inert atmosphere (nitrogen or argon).
Can be implemented.

[0084]

[Chemical 31]

[0085]   Alternatively,17The carbamate protecting group present in is suitable for its removal.
Removed under19May occur (Scheme 7). In addition, a suitable solvent (tetra
Hydrofuran, dichloromethane, benzene, etc.) reagents such as phosgene, cal
With bonyldiimidazole or dimethyl carbonate19The closed ring of 18 Will give the generation of.

[0086]

[Chemical 32]

Alternatively, compound 17 may be dehydrated to produce isopropene derivative 20 (Scheme 8). Suitable conditions for dehydration are the use of reagents such as acetic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonyl chloride or anhydride in a solvent such as pyridine, tetrahydrofuran, dichloromethane or benzene. The reaction can be carried out under an inert atmosphere (nitrogen or argon) at a temperature of 0 ° C. to the reflux temperature of the solvent, and a base such as 4-
The presence of dimethylaminopyridine, triethylamine, pyridine or di-isopropylethylamine may be required. The 20 is then exposed to an acidic condition to undergo a ring closure to produce 18 . Suitable conditions would be the use of an acid such as p-toluenesulfonic acid, methanesulfonic acid or camphorsulfonic acid in a solvent such as dichloromethane, benzene, toluene or tetrahydrofuran. The reaction is
It can be carried out under an inert atmosphere (nitrogen or argon) from 0 ° C to the reflux temperature of the solvent.

[0088]

[Chemical 33]

An alternative route to 18 is shown in Scheme 9. Then, H. Fukuium
i, M. Sugiyama, T .; Sakamoto, Chem. Pharm. B ull. , 37 (5): 1197 (1989) at a suitable temperature of 0 ° C. to the reflux temperature of the solvent under an inert atmosphere (nitrogen or argon) in an inert solvent (tetrahydrofuran, diethyl ether), organically. Metal reagents, eg G
Treatment of the previously described compound 21 with a linard reagent, an alkyl or arylzinc reagent, an alkyl or aryl lithium reagent yields a tertiary alcohol 22 . Compound 22 is then brought to the basic state effective for ring closure to form cyclocarbamate derivative 23 . Suitable conditions include treatment of 22 with a solvent, for example a base such as potassium hydroxide in ethanol or potassium t-butoxide in tetrahydrofuran. The reaction can be carried out at 0 ° C. to the reflux temperature of the solvent under an inert atmosphere (nitrogen or argon). Compound 23 may then be converted to the brominated derivative 24 . Suitable conditions include a solvent such as dichloromethane,
Treatment with bromine or N-bromosuccinimide in tetrahydrofuran or acetic acid. The reaction can be carried out in the presence of an additive such as silica gel at 0 ° C. to the reflux temperature of the solvent under an inert atmosphere (nitrogen or argon). Subsequent reaction of 24 with an aryl or heteroaryl boronic acid, a boronic anhydride or a trialkylstannane then affords the desired biaryl compound 18 . The reaction is carried out in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) or palladium acetate at 0 ° C. to the reflux temperature of the solvent under an inert atmosphere (nitrogen or argon) in a solvent such as acetone, ethanol, Can be carried out in benzene, toluene or tetrahydrofuran, and sodium carbonate,
Additives such as cesium fluoride or potassium phosphate may be required.

[0090]

[Chemical 34]

[0091]   Alternatively,23(Scheme 10) describes an inert solvent such as tetrahydrofuran.
Treated with reagents such as alkyllithium or lithium amide in orchid at low temperature
Then the boronic acid under the action of trimethyl borate or triisopropyl 25 (M = B (OH)₂) Or trimethyltin chloride or
Converted to stannane through reaction with bis (trimethyltin). Then
Radium catalysts such as tetrakis (triphenylphosphine) palladium (0)
Or in the presence of palladium acetate, and sodium carbonate, cesium fluoride
Or bromide or iodide, which may require additives such as potassium phosphate.
With reel or heteroaryl25Reaction of the desired thiophene cyclo
Carbamate18Will result in a conversion to

C. A method for synthesizing the thiophene thiocyclocarbamate compounds 26 and 27 shown in Scheme 11 is described below:

[0093]

[Chemical 35]

Thiophene thiocyclocarbamates 26 and 27 may be obtained directly by treating 5 and 18 , respectively, with phosphorus pentasulfide in refluxing pyridine.
Alternatively, 5 and 18 are Lawesson's reagents ([2
, 4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,4-disulfide]) to produce 26 and 27, respectively.

Method for producing thiazole cyclocarbamate derivative A method for producing a thiazole cyclocarbamate compound will be described below.

[0096]

[Chemical 36]

[0097]   Thus, thiazole28B. Golankiewicz and P.G.
Januszczyk,Tetrahedron, 41: 5989 (1985)
Prepared according to the procedure in the literature, Scheme 12. Then amine28 The reaction of the with a suitable chloroformate or carbonate is a protected amine 29 To generate. This can be a solvent such as dichloromethane, THF, benzene,
Chloroformate or carbonate derivative in siren or pyridine
, For example, methyl chloroformate, ethyl chloroformate, allyl chloroformate, chloroformate
2- (trimethylsilyl) ethyl or di-tert-butyl bicarbonate and compound 28 Can be accomplished by reacting. The reaction does not proceed from 0 ° C to the reflux temperature of the solvent.
Performed under an active atmosphere (nitrogen or argon) and a base such as 4-di
Methylaminopyridine, triethylamine, pyridine or di-isopropyl
The presence of ethylamine may be required. Then, at an appropriate temperature of 0 ° C to the reflux of the solvent.
Temperature, under an inert atmosphere (nitrogen or argon), under an inert solvent (THF, diethyl ether)
), An organometallic reagent such as Grinard reagent, alkyl or
Compounds for aryl-zinc reagents, alkyl or aryl lithium reagentsTwo 9 Exposure to alcoholThirtyCause Then the compoundThirtyIs effective for ring closure
Cyclocarbamate derivatives exposed to basic conditions31To get Suitable conditions are
Compounds with bases such as potassium hydroxide in solvents such as ethanolThirtyProcessing
including. The reaction is carried out at an inert atmosphere (nitrogen or argon) at a temperature of 0 ° C to the reflux temperature of the solvent.
) Can be carried out below.

[0098]

[Chemical 37]

Alternatively, the carbamate protecting group present on compound 30 may be prepared according to T.W. W. Gre
ene and P.E. G. M. Wuts, Protective Groups
in Organic Synthesis, second ed. , Wil
It may be removed under conditions suitable for its removal to give compound 32, as taught by ey-Interscience (1991). In addition, a suitable solvent (TH
F, dichloromethane, benzene, etc.) was reagents, such as phosgene, cyclization of compound 32 followed by carbonyldiimidazole or dimethyl carbonate would give the product of Compound 3 1.

[0100]

[Chemical 38]

Alternatively, if compound 30 is a tertiary alcohol, then it may be dehydrated to produce isopropene derivative 33 , Scheme 3. Suitable conditions for dehydration are the use of reagents such as acetic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonyl chloride or anhydride in a solvent such as pyridine, THF, dichloromethane or benzene. The reaction can be carried out under an inert atmosphere (nitrogen or argon) from 0 ° C. to the reflux temperature of the solvent and may require the presence of a base such as 4-dimethylaminopyridine, triethylamine, pyridine or di-isopropylethylamine. Then, the compound 33 is exposed to an acidic state to undergo ring closure to produce the compound 31 . Suitable conditions are: p in a solvent such as dichloromethane, benzene, toluene or THF
The use of acids such as toluene sulphonic acid, methane sulphonic acid or camphor sulphonic acid, and the reaction can be carried out under inert atmosphere (nitrogen or argon) from 0 ° C. to the reflux temperature of the solvent.

[0102]

[Chemical Formula 39]

Compound 31 may then be converted to bromide 34 , Scheme 15. Suitable conditions are exposure to bromine or N-bromosuccinimide in a solvent such as dichloromethane, THF or acetic acid, the reaction being carried out in the presence of an additive such as silica gel at 0 ° C. to the reflux temperature of the solvent in an inert atmosphere. (Nitrogen or argon)
You can do it below. Subsequent reaction with compound 34 with an aryl or heteroaryl boronic acid, a boronic anhydride or a trialkylstannane then affords the desired biaryl compound 35 . The reaction may require the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) or palladium acetate and an additive such as sodium carbonate, cesium fluoride or potassium phosphate, 0 ° C to solvent Can be carried out in a solvent such as acetone, ethanol, benzene, toluene or THF under an inert atmosphere (nitrogen or argon) at a reflux temperature of.

[0104]

[Chemical 40]

Alternatively, compound 31 is treated at low temperature with a reagent such as an alkyllithium or lithium amide in an inert solvent, eg THF, and then treated with a boronic acid (M = B) under the action of trimethyl borate or triisopropyl. (OH) ₂ ) 3
Converted to 6 or trimethyltin chloride or bis (trimethyltin) chloride
Scheme 16, converted to stannane under the action of. Then in the presence of a palladium catalyst, eg tetrakis (triphenylphosphine) palladium (0) or palladium acetate, and an additive such as sodium carbonate, cesium fluoride or potassium phosphate, which may require bromide or iodide. Subsequent reaction with an aryl or heteroaryl halide will result in the conversion to the desired compound 35 .

Amide Derivatives Method of Making Amidothiophene Derivatives A method of making thiophene derivatives is described below, Scheme 17.

[0107]

[Chemical 41]

The amine 37 is thus converted to a carbamate, eg tert-butyl carbamate, as described in scheme 1 for the preparation of compound 2 . Hydrolysis of ester 38 under basic conditions, such as lithium or sodium hydroxide in THF or methanol, then yields acid 39 . Conversion of the acid 39 to the acid chloride 40 is accomplished under standard conditions, thionyl chloride or oxalyl chloride alone or in the presence of a solvent such as dichloromethane and a catalytic amount of an additive such as N, N-dimethylformamide. It Compound 40 is then reacted with diazomethane or trimethylsilyldiazomethane in an inert solvent such as THF or dichloromethane and the product diazoketone 41 is then rearranged in the presence of silver (I) oxide to form acid 42 . Treatment of compound 42 under conditions that specifically remove protection of the carbamate functionality, eg, acidic conditions, then results in cyclization to produce compound 43 . Then, at a temperature of −78 ° C. to the boiling point of the solvent, under an inert atmosphere (nitrogen or argon), under basic conditions, for example, butyllithium in the presence of a solvent such as N, N, N, N-tetramethylenediamine in THF. Of the compound 43 with an alkylating agent such as iodide, bromide, alkyl p-toluenesulphonic acid or methanesulphonate, or iodide, bromide, p-toluenesulphonic acid or a bis-alkyl methanesulphonate. The reaction produces the alkylated derivative 44 .

Method of Making Thiazole Derivatives A method of making thiazole derivatives is described below, Scheme 18.

[0110]

[Chemical 42]

[0111]   At room temperature, use basic conditions such as lithium hydroxide in THF or methanol.
Is an ester under sodium29Hydrolysis of acid45Cause acid45Acid chloride 46 Conversion to standard conditions such as thionyl chloride or oxalyl chloride
Or a solvent such as dichloromethane and a catalytic amount of N, N-dimethylform
It is carried out in the presence of additives such as muamide. Then the compound46Is inactive
Diazomethane or Trimethyi in a solvent such as THF or dichloromethane
Rezyldiazomethane, then the product diazoketone47Is silver oxide
The acid is rearranged in the presence of (I)48To generate. Then the carbamate functional group
Compounds under conditions that specifically remove protection, eg under acidic conditions48Processing of cyclization
Heterocyclic compound49To generate. Then, the temperature is −78 ° C. to the boiling point of the solvent.
Under an inert atmosphere (nitrogen or argon) under basic conditions such as lysis.
Butyl in the presence of a medium such as N, N, N, N-tetramethylenediamine in THF
Under lithium, alkylating agents such as iodide, bromide, p-toluenesulfonic acid are also available.
Alkyl methanesulfonate or iodide, bromide, p-toluenesulfo
Compound with acid or bis-alkyl methanesulfonate49The reaction with
Heterocyclic compoundFiftyTo generate. Then the compoundFiftyIs the bromide51Converted to
You may Suitable conditions include a solvent such as dichloromethane, THF or acetic acid.
Medium, exposure to bromine or N-bromosuccinimide, the reaction was
In the presence of additives such as cagel, an inert atmosphere (nitrogen
Or argon). Aryl or heteroaryl boronic acid,
Compounds with boronic anhydride or trialkylstannanes51Subsequent reaction with
Then the desired biaryl compound52To get The reaction is a palladium catalyst, eg
For example, tetrakis (triphenylphosphine) palladium (0) or para acetate
In the presence of sdium and sodium carbonate, cesium fluoride or potassium phosphate
Additives, such as aluminum, may be required and may be used at an inert atmosphere (from 0 ° C to the reflux temperature of the solvent).
Nitrogen or argon) under a solvent such as acetone, ethanol, benzene,
It can be carried out in toluene or THF. Thione derivatives, compounds53Is the reflux pipe
In lysine52Can also be obtained directly by treating P with phosphorus pentasulfide. Ah
Rui is also52Treated with Lawesson's reagent in refluxing pyridine53To
Occurs.

The anti-progestin compounds of the formulations of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts are
Non-limiting examples include salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and optionally organic acids such as acetic acid, oxalic acid, succinic acid and maleic acid. Other salts are alkali metal or alkaline earth metal, in the form of esters, carbamates, and other conventional "prodrug" forms that convert to the active moiety in vivo when administered in such forms. , Salts with, for example, sodium, potassium, calcium or magnesium.

These methods of treatment may be for contraception or secondary amenorrhea, dysfunctional bleeding, uterine leiomyoma, endometriosis; polycystic ovary syndrome, endometrium, ovary, breast, colon, prostate. It may be used for the treatment and / or prevention of carcinoma and adenocarcinoma of, or for minimizing side effects or periodic menstrual bleeding. Further uses of the invention include stimulation of food intake.

When the combined compounds are used for the above applications, they may also be combined with one or more pharmaceutically acceptable carriers or additives such as solvents, diluents and the like. Well, and tablets, capsules, dispersible powders, granules, or suspensions containing, for example, about 0.05-5% suspending agents, such as syrups containing about 10-50% sugar, and, for example, About 20-50 ethanol
% In an elixir, and similar forms, orally,
Alternatively, it may be administered parenterally in the form of a sterile injectable solution or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% by weight of active ingredient, more usually from about 5 to 60% by weight, in combination with a carrier.

These active compounds may be administered orally as well as by the intravenous, intramuscular or subcutaneous routes. Solid carriers may include starch, lactic acid, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers may be sterile water, as appropriate to the nature of the active ingredient and the particular dosage form desired. , Polyethylene glycol, nonionic surfactants and edible oils such as corn, peanut and sesame oils. Adjuvants conventionally used in the manufacture of pharmaceutical compositions may advantageously include, for example, flavoring agents, coloring agents, preservatives, and antioxidants such as vitamin E, ascorbic acid, BHT and BHA. .

Suitable pharmaceutical compositions from the standpoint of ease of manufacture and administration are solid compositions, especially tablets and hard and soft capsules. Oral administration of the compound is preferred.

These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as the free base or a pharmaceutically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl cellulose. The dispersant is glycerol in oil,
It can be manufactured in liquid polyethylene glycol and mixtures thereof. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Dosage forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and mold. The carrier is a solvent or dispersion medium containing, for example, water, ethanol (eg glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils.

The following non-limiting examples are specific illustrations of representative compound 5 .

Example 1 6- (3-chlorophenyl) -1,4-dihydro-4,4-dimethyl- 2H-thieno [2,3-d] [1,3] oxazin-2-one 2- (3 -Chlorobenzyl ) acetaldehyde To a 25 ° C solution of 3-chlorostyrene (10.0 g, 72.15 mmol) in anhydrous CH ₂ Cl _{2 was} added Pb (OAc) ₄ (35.2) in trifluoroacetic acid (150 ml).
g, 79.4 mmol) of a well-stirred solution was added dropwise. The reaction was completed within 30 minutes of addition, and after stirring for an additional 30 minutes, the mixture was poured into water and ether (3X
) And the combined organic layers are washed with saturated NaHCO ₃ solution, water and dried (Mg.
SO ₄ ) and concentrated to a volume of about 15 ml and used directly for the subsequent reactions described below.

[0121] 2-Amino-5- (3-chloro - phenyl) - thiophene-3-carboxylic Sanme Chiruesuteru methanol, the crude aldehyde which was prepared earlier, sulfur (2.55 g, 79.4
4 mmol), methyl cyanoacetate (7.88 g, 79.44 mmol), morpholine (6.92 g, 79.44 mmol) and the resulting reaction mixture was refluxed for 16 hours. Unreacted sulfur was filtered off and the filtrate evaporated to leave a black residue. Extract the residue with ether, and washed with H ₂ O. Crystallized from ether / hexane (1: 5) to give white crystals (3.85g, 14.3m).
mol, 50%), mp 85-87 °. ¹ H NMR (DMSO-d ₆ ) δ 3.75 (s, 3H), 7
.18-7.27 (m, 1H), 7.31-7.42 (m, 3H), 7.53 (s, 1H), 7.62 (s, 1H); MS (+ APCI) m / z268
_{(M + H); C 12} H 10 ClNO 2 Calculated elemental analysis for S: C, 53.83, H, 3.76, N, 5.23.
Found: C, 53.57, H, 3.37, N, 5.00.

[0122] 2-allyloxycarbonyl-amino-5- (3-chloro - phenyl) - Chiofu E down-3-carboxylic acid methyl ester To 1,2-dichloroethane (50ml) of 2-amino-5- (3-chloro −
Phenyl) -thiophene-3-carboxylic acid methyl ester (2 g, 7.5 mmo
l) solution, under nitrogen at room temperature allyl chloroformate (1.6 ml, 15.1 mm
ol) was added. The reaction mixture was heated under reflux under nitrogen for 18 hours, cooled to room temperature and treated with saturated aqueous sodium bicarbonate solution (100 ml). The organic layer was separated and the aqueous layer was extracted with methylene chloride (3x20ml). The combined organic layers were washed (brine), dried (MgSO _4). After removal of solvent, the residue was purified by flash silica gel column (hexane: ethyl acetate / 7: 1) to give the subtitle compound (2.14 g, 81%) as an off-white solid: ¹ H-NMR ( DMS
Od ₆ ) δ 10.2 (s, 1H), 7.73 (t, 1H, J = 1.7Hz), 7.66 (s, 1H), 7.57 (dt, 1H, J = 7.7, 1
.7Hz), 7.41 (t, 1H, J = 7.7Hz), 7.34 (dt, 1H, J = 6.8, 1.6Hz), 6.01 (m, 1H), 5.41 (
dd, 1H, J = 7.3, 1.6Hz), 5.29 (dd, 1H, J = 10.5, 1.3Hz), 4.74 (d, 2H, J = 5.5Hz), 3
.84 (s, 3H). Elemental analysis for C ₁₆ H ₁₄ ClNO ₄ S: C, 54.63, H, 4.01, N, 3.
98. Found: C, 54.56, H, 3.92, N, 3.89.

2-Arenoxycarbonylamino-5- (3-chloro-phenyl) -thiophene-3-carboxylic acid methyl ester (0.1 g, 0.28 mmol) in anhydrous THF.
) Solution at room temperature under nitrogen, methylmagnesium bromide (3 in diethyl ether).
． 0M, 1.5 ml, 4.5 mmol) solution was added. After stirring for 20 minutes at room temperature under nitrogen, the reaction mixture was treated with brine (10 ml), followed by the addition of 1N aqueous HCl solution. Ethyl acetate (20 ml) was added and the organic layer was separated, brine (
5 ml) and dried over MgSO ₄ . After removal of solvent, the residue was purified by flash column (silica gel, hexane: ethyl acetate / 5: 1),
The carbinol used in the next step was obtained without further purification and identification.

A mixture of the above crude carbinol and potassium hydroxide (excess amount) in ethanol was stirred under nitrogen at room temperature overnight. The reaction solution was then acidified by addition of cold 1N HCl aqueous solution. Ethyl acetate (20 ml) was added and the organic layer was separated,
Washed with brine (5 ml), and dried (MgSO _4). After removal of solvent, the residue was purified by silica gel column (hexane: ethyl acetate / 2: 1) to give the title compound as an off-white solid (16 mg, 19% over 2 steps):
mp149-150 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 10.69 (s, 1H), 7.64 (t, 1H, J = 1.8 Hz),
7.49 (s, 1H), 7.47 (dt, 1H, J = 7.7, 1.4Hz), 7.39 (t, 1H, J = 7.8Hz), 7.29 (dt, 1H,
.. J = 7.8, 1.3Hz) , 1.61 (s, 6H) MS (EI) m / z293 / 295 (M +) C 14 H 12 ClNO 2 Calculated elemental analysis for S: C, 57.24, H, 4.12, N, 4.77. Found: C, 57.27, H, 4.25, N, 4.
66.

Example 2 6- (3-chlorophenyl) -1,4-dihydro-4,4-dimethyl- 2H-thieno [3,2-d] [1,3] oxazin-2-one 3-chloro- A solution of 3- (3-chloro-phenyl) -acrylonitrile POCl ₃ was slowly added into anhydrous DMF over 20 minutes and the temperature was maintained around 30 ° C. A solution of 3'-chloroacetophenone in anhydrous DMF was added to the above solution and the reaction temperature was raised to about 50 ° C. Hydroxylamine HCl was added portionwise to the reaction solution over 1 hour. A water volume of 500 ml was added to form a precipitate, stirred for 1 hour, and the precipitate was collected on a Buchner funnel, washed with H ₂ O and dried to give a yellow crystalline compound, mp 60-62 ° C.
. ¹ H NMR (DMSO-d ₆ ) δ 1.60 (s, 6H), 7.30 (d, 1H, J = 8.41Hz), 7.41 (d, 1H, J = 8.41Hz)
), 10,47 (s, 1H); MS (+ APCI) m / z213 (M + H); Calculated by elemental analysis for C ₉ H ₉ ClN ₂ O ₂ : C, 50.84, H, 4.27, N , 13.17. Found: C, 50.99, H, 4.28, N, 12.98.

[0126] 3-amino-5- (3-chloro - phenyl) - thiophene-2-carboxylic Sanme Chiruesuteru sodium pellets to form a NaOMe was added slowly to a methanol solution in situ, then methyl thioglycolate It was added to the methanol solution over 20 minutes. 3-chloro-3- (3-chloro-phenyl)-in methanol
The acrylonitrile solution was added slowly and refluxed for 1 hour. The reaction mixture is cooled to room temperature and the methanol is concentrated to 100 ml and water 200 m.
l, stirred for 30 minutes, and the yellow precipitate collected, washed with water several times,
A yellow crystalline compound was obtained, mp 92-95 ° C. ¹ H NMR (DMSO-d ₆ ) δ 1.60 (s, 6H), 7
.30 (d, 1H, J = 8.41Hz), 7.41 (d, 1H, J = 8.41Hz), 10,47 (s, 1H); MS (+ APCI) m / z213 (
_{. M + H); C 9} H 9 ClN 2 O 2 Calculated elemental analysis for: C, 50.84, H, 4.27 , N, 13.17 Found: C, 50.99, H, 4.28 , N, 12.98.

[0127] 3-allyloxycarbonyl-amino-5- (3-chloro - phenyl) - Chiofu E emission-2-carboxylic acid methyl ester in toluene (200 ml) of 3-amino-5- (3-chloro - phenyl) - thiophene 2-Carboxylic acid methyl ester (15 g, 56.0 mmol) solution,
A solution of allyl chloroformate (8.10 g, 67.2 mmol) in toluene (5 ml) was added and the resulting reaction solution was heated under reflux for 3 hours. Toluene was removed and the crystals were collected and washed with ether / hexane to give a yellow crystalline compound, mp 101-103 ° C. ¹ H NMR (DMSO-d ₆ ) δ3.85 (s, 3H), 4.68-4.71 (d, 2H,
J = 5.46Hz), 5.26-5.30 (dd, 1H, J = 1.35, 9.84Hz), 5.36-5.42 (dd, 1H, J = 1.57, 1
5.68Hz), 5.96 (m, 2H), 7.50-7.52 (m, 2H), 7.67-7.71 (m, 1H), 7.79 (s, 1H), 8.10 (
s, 1H); MS (+ APCI) m / z 352 (M + H); Calculated by elemental analysis for C ₁₆ H ₁₄ ClNO ₄ S: C, 5
4.63, H, 4.01, N, 3.97. Found: C, 54.05, H, 4.17, N, 3.84.

[0128] [5- (3-chloro - phenyl) -2- (1-hydroxy-1-methyl - ethyl Le) - thiophen-3-yl] - in anhydrous THF in the carbamic acid allyl ester at room temperature (30 ml) 3- Allyloxycarbonylamino-
5- (3-chloro-phenyl) -thiophene-2-carboxylic acid methyl ester (
To a 5.3 g, 15.1 mmol) solution was added 3.0 MMeMgI (20.
1 ml, 60.24 mmol) solution was added. After 30 minutes, the reaction was reacted with H ₂ O (10
gradually stopped in ml), and extracted with ether (200 ml), washed with brine, and dried (MgSO _4), concentrated and chromatographed (hexane: ether, 1: 4) was: Mp60- 61 ° C .; ¹ H NMR (DMSO-d ₆ ) δ1.52 (s, 6H),
4.59-4.61 (d, 2H, J = 5.35Hz), 5.22-5.36 (m, 2H), 5.91-6.04 (m, 2H), 7.33-7.67 (
m, 5H), 8.89 (s , 1H); MS (EI) m / z351 / 353 (M + H); C 17 H 18 ClNO 3 Calculated elemental analysis for S: C, 58.03, H, 5.16, N, 3.98. Found: C, 58.17, H, 5.16, N, 3.97.

6- (3-chlorophenyl) -1,4-dihydro-4,4-dimethyl-2H- thieno [3,2-d] [1,3] oxazin-2-one anhydrous THF (5.0 ml) To a solution of [5- (3-chloro-phenyl) -2- (1-hydroxy-1-methyl-ethyl) -thiophen-3-yl] -carbamic acid allyl ester (.12 g, .34 mmol) in medium, KO ^t Bu. (0.076g,
0.068 mmol) and stirred for 15 minutes, quenched with H ₂ O, and in situ crystallization was carried out by adding a minimum amount of MeOH to the solution. White crystals were collected on a Buchner funnel, mp123-125
° C. ¹ H NMR (DMSO-d ₆ ) δ 1.64 (s, 6H), 7.05 (s, 1H), 7.37-7.48 (m, 2H), 7.53-7.56 (
s, 1H), 7.67-7.68 (m , 1H), 10.41 (s, 1H); MS (EI) m / z293 / 295 (M + H); C 17 H 18 ClNO 3 S
Calculated by elemental analysis for: C, 57.24, H, 4.12, N, 4.77. Found: C, 56.93, H,
3.92, N, 4.97.

Example 3-Pharmacology The progestational activity of the compounds of the present invention is demonstrated by the following PRE-in CV-1 cells.
It was evaluated in a luciferase assay. In vitro potency is in the range 0.
Present at 01 nM-10,000 nM. In vivo efficacy is 1m
It is expected to be present at g / kg to 30 mg / kg.

The purpose of this assay is to determine the progestation of a compound based on its effect on PRE-luciferase reporter activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids.
gestational or antiprogestational
onal) to determine efficacy. The material method used in the assay is as follows.

A. Medium : Growth medium was as follows: 10% (v / v) fetal bovine serum (
Heat inactivation), 0.1 mM MEM non-essential amino acid, 100 U / ml penicillin, 1
00 mg / ml streptomycin, and 2 mM GlutaMax (GIBC
O, BRL) containing DMEM (BioWhittaker). The experimental medium was as follows: 10% (v / v) charcoal depleted fetal bovine serum (heat inactivated),
0.1 mM MEM non-essential amino acid, 100 U / ml penicillin, 100 mg /
ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL
) -Containing DMEM (BioWhittaker), without phenol red.

B. Cell Culture, Transfection, Treatment and Luciferase Assay Storage CV-1 cells are maintained in growth medium. Co-transfection consisted of 1.2 × 10 ⁷ cells in 250 ml, 5 mg of pLEM plasmid with hPR-B inserted at SphI and BamHI sites, 10 mg of pGL3 plasmid with two PRE upstream of the luciferase sequence, and sonication as carrier DNA. Performed with 50 mg of treated calf thymus DNA. Electroporation was performed on a Biorad Gene Pulser II 260
Performed at V and 1,000 mF. After electroporation, cells were resuspended in growth medium and 40,000 in 200 μl in 96 well plates.
Plated at 0 cells / well. Following overnight culture, the medium is replaced with experimental medium. The cells are then treated with a reference or test compound in experimental medium. The compounds are tested for anti-pregnancy activity in the presence of 3nM progesterone. Twenty-four hours after the treatment, the medium was discarded and the cells were washed with D-PBS (GI
Wash 3 times with BCO, BRL). Cell lysis buffer (Promega
, Madison, WI) 50 μl was added to each well and the plate was
iter Plate Shaker (Lab Line Instrumen)
t, Inc. ) For 15 minutes. Luciferase activity is Prome
It is measured using a luciferase reagent manufactured by Ga.

C. Analysis of the results : Each process consists of at least 4 parallels. Log transformed data are used for analysis of variability and non-linear dose response curve fits for both agonist and antagonist modes. Huber weighting is outlier (o
It is used to downweight the effect of the utlier. EC ₅₀ or an IC ₅₀ value is calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variation and non-linear response analysis.

D. Reference compounds : progesterone and trimegeston are reference progestins, and RU
486 is the reference anti-progestin. All reference compounds are completely dose - used in the response curve, and EC ₅₀ or an IC ₅₀ value is calculated.

[0136]

[Table 1]

[0137]

[Table 2]

Pre-gestational activity: Compounds that significantly (p <0.05) increase PRE-luciferase activity compared to vehicle controls are considered active.

Anti-pregnancy activity: A compound that significantly (p <0.05) reduces 3nM progesterone-induced PRE-luciferase activity.

EC ₅₀ : Compound concentration that gives a half-maximal increase in PRE-luciferase activity (default-nM), including SE.

IC ₅₀ : Compound concentration containing a half maximal decrease in 3nM progesterone-induced PRE-luciferase activity (default-nM), including SE. All of the above publications cited herein are hereby incorporated by reference. Although the present invention has been described with respect to certain preferred embodiments,
It will be appreciated that modifications and variations can be made without departing from the spirit of the invention. Such modifications are considered to fall within the scope of the appended claims.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, SD, SL, SZ, TZ, UG, ZW ), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, C N, CR, CU, CZ, DE, DK, DM, DZ, EE , ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, K P, KR, KZ, LC, LK, LR, LS, LT, LU , LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, S G, SI, SK, SL, TJ, TM, TR, TT, TZ , UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Ji, Lin             92129, California, United States             Nde Diego Lawn Road 7794 (72) Inventor John Jones, Todd Kay             United States California California State 92075             Lana Beach Marvie Drive 546 (72) Inventor Tegley, Christopher M             91360, California, United States             Thousand Oaks Thunderhead             478 (72) Inventor Santeira, Arthur A.             19083 Ha, Pennsylvania, United States             Burtown Suelen Drive 1737 (72) Inventor Viet, Andrew Kyu             19082, Pennsylvania, United States             Tuparder Beverly Boulevard             250 ・ Apartment L-200 (72) Inventor Tuang, Puen             19403 Ohio, Pennsylvania, United States             Doubon Oriole Court 7004 (72) Inventor Fentham, Andrew             19087, Pennsylvania, United States             Ain Treff Annie Lane 779 (72) Inventor Blobel, Jei             United States New Jersey 08648             Lawrenceville Rosetree Lane 15 (72) Inventor Edwards, The Ames P             92129, California, United States             Ndeiego Hesby Court 8723 F term (reference) 4C072 AA01 BB02 CC01 CC11 CC16                       EE05 FF19 GG07 UU01                 4C084 AA18 NA14 ZA86                 4C086 AA01 AA02 BC72 DA08 MA02                       MA04 NA14 ZA86

Claims (19)

[Claims] 1. A) Phase I of a 14- to 24-day daily dose unit of a progestational drug equal to about 35 to about 100 μg levonorgestrel in progestational activity; b) Formula I: [In the formula, A and B are independent substituents selected from S, CH, or N, provided that when A is S, B is CH or N; Is CH or N; and A and B cannot both be CH; and when A and B are both equal to N, one N is optionally substituted by C ₁ -C ₆ alkyl groups R ₁ and R ₂ are H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, substituted C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, COR ^A or NR ^B COR ^A , an independent substituent selected from the group or it; or, R ¹ and ² is fused, a) optionally spirocyclic alkyl ring 3-8 membered to be replaced; spirocyclic alkenyl ring 3-8 membered being optionally substituted or b); or c) O , S and N to form an optionally substituted 3-8 membered spirocyclic ring containing 1 to 3 heteroatoms; R ^A is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ^B is , H, C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl; R ³ is H, OH, NH ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₁ -C ₆ alkenyl, alkynyl or location Alkynyl or COR ^C; R ^C is, H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ⁴ is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below: Wherein X is halogen, CN, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ thioalkyl, substituted C ₁ -C ₃ thioalkyl, C ₁ -C ₃ aminoalkyl, substituted C ₁ -C ₃ aminoalkyl, NO _2, C ₁ -C ₃ perfluoroalkyl, 5- or 6-membered heterocyclic ring containing 1-3 heteroatoms Shikiwa, COR ^D, selected from OCOR ^D, or NR ^E COR ^D; R ^D is, H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ^E is, H, be a C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl; Y and Z are H, halogen, CN, NO _2, C ₁ -C ₃ alkoxy, or independently selected from C ₁ -C ₃ alkyl or C ₁ -C ₃ thioalkyl; or, R ⁴ is selected O, S, SO, from SO ₂ or NR ⁵ A 5- or 6-membered ring having 1, 2 or 3 heteroatoms represented by H, halogen, C
N, NO ₂ and C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl, COR ^F, or NR ^G COR independent substituents selected from ^F 1 or 2
Optionally substituted by a group; R ^F is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy. , C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ^G is H, C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl; R ⁵ is H or C ₁ -C is ₃ alkyl; W is, antiprogestin compound of O or a chemical bond, or a pharmaceutically acceptable salt thereof, a daily dose units 1-11 days at a daily dose of about 2~50mg of Second phase of minutes; and c) optionally a daily dose unit of an orally and pharmaceutically acceptable placebo for the remaining 28 consecutive days without antiprogestin, progestin or estrogen being administered. 3 phase: a first, second and third phases of the total daily equal consecutive 28 days in a dose unit 28, a method of contraception comprising administering to female pregnancy age. 2. The pre-gestational drug is levonorgestrel and the anti-progestin compound is A and B are independent substituents S, CH or N, provided that when A is S, B is CH or N; and when B is S, A is CH or N; and A and B cannot both be CH; and when A and B are both equal to N, one N is optionally May be substituted with a C ₁ -C ₆ alkyl group; R ¹ is H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, be a COR ^A, or NR ^B COR ^A; R ² is, H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl,
Substituted C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ substituted alkynyl, C ₃
-C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, COR ^A or NR ^B COR ^A ; or R ₁ and R ₂ are fused. A) an optionally substituted 3-8 membered spirocyclic alkyl ring; or b) an optionally substituted 3-8 membered spirocyclic alkenyl ring; or c) a group of O, S and N. Form a optionally substituted _3- to 8-membered spirocyclic ring containing 1 to 3 heteroatoms selected from: R ^A is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ^B is, H, C ₁ - C ₃ alkyl or substituted C ₁ - Is ₃ alkyl; R ³ is, H, OH, NH _2, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₁ -C ₆ alkenyl, alkynyl or substituted alkynyl Or COR ^C ; R ^C is H, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl, aryl, substituted aryl, C ₁ -C ₄ alkoxy, substituted C ₁ -C ₄ alkoxy, C _1-. C ₄ aminoalkyl or substituted C ₁ -C ₄ aminoalkyl; R ⁴ is a trisubstituted benzene ring containing substituents X, Y and Z as shown below: Wherein X is halogen, CN, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ thioalkyl, substituted C ₁ -C ₃ thioalkyl, C ₁ -C ₃ aminoalkyl, substituted C ₁ -C ₃ aminoalkyl, NO _2, C ₁ -C ₃ perfluoroalkyl, 5 membered heterocyclic ring containing 1-3 heteroatoms , COR ^D, selected from OCOR ^D, or NR ^E COR ^D; R ^D is, H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ^E is, H, be a C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl; Y and Z is H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, or is an independent substituent selected from C ₁ -C ₃ alkyl or C ₁ -C ₃ group comprising thioalkyl; or, R ⁴ is, O, S, SO, SO ₂ or NR a 5 or 6-membered ring containing three, two or heteroatoms selected from ^5, 5 or 6-membered ring, H, halogen, CN, NO ₂ and C ₁ -C ₃ alkyl or C ₁ - Optionally substituted by 1 or 2 independent substituents selected from C ₃ alkoxy; R ⁵ is H or C ₁ -C ₃ alkyl; W is O or a chemical bond. 2. The method of claim 1 selected from the compound of Formula I of 1 or a pharmaceutically acceptable salt thereof. 3. The pre-pregnant drug is levonorgestrel and the anti-progestin compound is: A and B are independent substituents from the group comprising S, CH or N, provided that A is S. In some cases, B is CH or N; and when B is S, A is CH or N; and A and B cannot both be CH; R ¹ = R ² and C ₁ − C ₃ alkyl, substituted C ₁ -C ₃ alkyl, or R ₁
And R ₂ is selected from the group comprising spirocyclic alkyl constructed by condensing R ₂ to form a 3-6 membered spirocyclic ring; R ³ is H, OH, NH ₂ , C _1-. C ₆ alkyl, substituted C ₁ -C ₆ alkyl or CO
R ^C ; R ^C is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; R ⁴ is a disubstituted benzene ring containing substituents X and Y as shown below: Chemical 4] Wherein X is halogen, CN, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, NO ₂ , C _1-.
C ₃ perfluoroalkyl, a 5 membered heterocyclic ring containing 1-3 heteroatoms,
Or selected from the group containing C ₁ -C ₃ thioalkyl; Y is selected from the group of H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl or C ₁ -C ₃ thioalkyl. Is a substituent at the 4'or 5'position; or, R ⁴ is a structure shown below: A 5-membered ring having U is O, S or NR ⁵ , R ⁵ is H or C ₁ -C ₃ alkyl or C ₁ -C ₄ CO ₂ alkyl; and X ′ is halogen. , CN, NO ₂ , C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy; Y'is H or C ₁ -C ₄ alkyl; or R ⁴ is of the structure: A 6-membered ring having: X ¹ is N or CX ² ; X ² is halogen, CN or NO ₂ ; W is O or a chemical bond. The method of claim 1, which is selected from a compound, or a pharmaceutically acceptable salt thereof. 4. The progestational drug is levonorgestrel and the antiprogestin compound is R ¹ = R ² and C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, or R ₁
And A, B, R ³ , R ^C , R ⁴ , selected from the group comprising spirocyclic alkyl constructed by condensing R ₂ and R ₂ to form a 3-6 membered spirocyclic ring; X, Y, U, R ⁵ , X ', Y', X ¹ , X ² , R ⁶
, R ⁷ , R ⁸ , R ⁹ and W are as defined in claim 3, selected from the compound of formula I of claim 1 or a pharmaceutically acceptable salt thereof. Method. 5. The pre-pregnant drug is levonorgestrel and the anti-progestin compound R ₁ and R ₂ are fused to form a 3-6 membered spirocyclic ring; and A, B, R ³ , R ^C , R ⁴ , X, Y, U, R ⁵ , X ′, Y ′, X ¹ , X ² , R ⁶
, R ⁷ , R ⁸ , R ⁹ and W are as defined in claim 3, selected from the compound of formula I of claim 1 or a pharmaceutically acceptable salt thereof. Method. 6. A) Phase I of a 14 to 24 day daily dose unit of a progestational drug equal to about 35 to about 100 μg of levonorgestrel in progestational activity; b) Formula: [Wherein R ₁ and R ₂ are H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, substituted C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, independently selected from the group consisting of substituted aryl, heterocyclic, substituted heterocyclic, COR ^a, or NR ^B COR ^a Alternatively, R ¹ and R ² are fused to form a) a 3 to 6 membered spirocyclic alkyl ring; or b) a 3 to 6 membered spirocyclic alkenyl ring; R ³ is H, OH, NH ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₁ -C ₆ alkenyl, alkynyl or substituted alkynyl or COR ^C. There; R ^B is, H, C ₁ -C ₃ alkyl if Is a substituted C ₁ -C ₃ alkyl; R ^C is, H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ Alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ⁴ is a tri-substituted benzene ring containing substituents X, Y and Z as shown below: Wherein X is halogen, CN, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ thioalkyl, substituted C ₁ -C ₃ thioalkyl, C ₁ -C ₃ aminoalkyl, substituted C ₁ -C ₃ aminoalkyl, NO _2, C ₁ -C ₃ perfluoroalkyl, 5- or 6-membered heterocyclic ring containing 1-3 heteroatoms Shikiwa, COR ^D, selected from OCOR ^D, or NR ^E COR ^D; R ^D is, H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; R ^E is, H, be a C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl; Y and Z are H, halogen, CN, NO _2, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ antiprogestin compound of chosen] independently from thioalkyl, or a pharmaceutically acceptable salt thereof, a daily dose of about Phase II for daily dosage unit 1 to 11 days at 2 to 50 mg; and c) optionally orally and pharmaceutically for the remaining 28 consecutive days without antiprogestin, progestin or estrogen being administered. Phase 3 of an acceptable placebo daily dose unit, which is to be administered to women of pregnancy age for 28 consecutive days, where the total daily dose units of Phases 1, 2, and 3 are equal to 28. Contraceptive methods including. 7. The anti-progestin compound is 6- (3-chlorophenyl) -1.
, 4-Dihydro-4,4-dimethyl-2H-thieno [2,3-d] [1,3] oxazin-2-one, or a pharmaceutically acceptable salt thereof. 8. The pre-pregnant drug is levonorgestrel, norgestrel,
Desogestrel, 3-keto desogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, drospirenone, nomegestrol or (17
The method of claim 1, wherein the method is selected from the group of -deacetyl) norgestimate. 9. A) 21st day of the first dose unit of a pre-pregnant drug equivalent to about 35 to about 100 μg of levonorgestrel in pre-gestational activity Phase 1 for 21 days; b) each daily dose unit is about a daily dose. A second phase of the anti-progestin compound according to claim 1 in a daily dosage unit of 3 days containing 2 to 50 mg of the anti-progestin compound; and c) optionally a 28-day cycle following the first and second phases. 4. A daily dose unit of an orally and pharmaceutically acceptable placebo for 4 days to be administered after and after each of: Method 1. 10. A) Levonorgestrel about 35-35 in pre-gestational activity
Progestational drug equivalent to about 150 μg, and daily dose range of about 10 to about 35 μg
Phase 1 of a daily dosage unit of 18 to 21 days of ethinyl estradiol in
And b) a second phase of 1 to 7 daily dose units of the antiprogestin of claim 1 at a daily dose of about 2 to 50 mg; and c) optionally for each remaining 28 consecutive days. Orally and Pharmaceutically Acceptable Placebo: A method of contraception comprising administering to a woman of pregnancy age for 28 consecutive days. 11. A) Levonorgestrel about 35-35 in pre-gestational activity
Progestational drug equivalent to about 100 μg, and daily dose range of about 10 to about 35 μg
21 days of a daily dosage unit of ethinyl estradiol in 21 days; and b) a second day of the antiprogestin of claim 1 at a daily dose of about 2 to 50 mg. 11. The method of contraception according to claim 10, optionally comprising administering to a female of pregnancy age for 28 consecutive days of a daily dose unit of 4 days of an orally and pharmaceutically acceptable placebo for 3 days. 12. A) Levonorgestrel about 35-35 in pre-pregnancy activity.
A daily dose unit 1 containing a progestational drug in a daily dose equal to about 150 μg, and ethinyl estradiol in a daily dose range of about 10 to about 35 μg
Phase 1 for 8-21 days; b) A daily dosage unit 1 to 1 in which each daily dosage unit contains the antiprogestin of claim 1 at a concentration of 2 to 50 mg and ethinyl estradiol at a concentration of about 10 to about 35 μg. 7 days of phase 2; and c) optionally phase 3 of an orally and pharmaceutically acceptable placebo daily dose unit: and a total daily dose unit of 28, continuous A method of contraception comprising administering to a woman of pregnancy age for 28 days. 13. A) a pre-pregnant drug at a daily dose equal to about 35 to about 100 μg levonorgestrel in each pre-gestational activity, and ethinyl estradiol in a daily dose range of about 10 to about 35 μg. A daily dosage unit containing 21 days of the first phase; b) A daily dose containing the anti-progestin of claim 1 at a concentration of 2 to 50 mg and ethinyl estradiol at a concentration of about 10 to about 35 μg. 3 days of phase 2; and c) optionally, a daily dose unit of 4 days of oral and pharmaceutically acceptable placebo: phase 3 of: Administered to women of pregnancy age for 28 consecutive days. 13. The method of contraception according to claim 12, comprising: 14. A) Levonorgestrel about 35 to 35 in pre-pregnancy activity
The first phase of a progestational drug daily dosage unit for 14 to 21 days equal to about 150 μg; b) each daily dosage unit containing an antiprogestin compound at a daily dosage of about 2 to 50 mg. Second daily dose unit of anti-progestin compound for 1 to 11 days
Phase; and c) a third phase of a daily dose unit of an orally and pharmaceutically acceptable placebo: and the total number of daily dose units in the first, second and third phases is equal to 28 , A pharmaceutically useful kit adapted for daily oral administration. 15. A) Levonorgestrel about 35-35 in pre-pregnancy activity
21 phases of 21 daily dose units of progestational drug equal to about 150 μg; b) each daily dose unit contains antiprogestin at a daily dose of about 2 to 50 mg. Daily dosage unit of 3 days of the second phase; and c) an oral and pharmaceutically acceptable placebo 4 day dosage unit of the third phase of: A pharmaceutically useful kit adapted for. 16. A) Levonorgestrel about 35-35 in pre-gestational activity
Progestational drug equivalent to about 150 μg, and daily dose range of about 10 to about 35 μg
Phase 1 for 18 to 21 days of daily dose unit of ethinyl estradiol in; b) Phase 2 to daily dose unit of 1 to 7 days of the antiprogestin of claim 1 at a daily dose of about 2 to 50 mg; and c) Orally and pharmaceutically acceptable placebo daily dose units 0 to 9 days of the third phase: including a total of 28 daily dose units in the first, second and third phases. A pharmaceutically useful kit adapted for daily oral administration equal to. 17. A) Levonorgestrel about 35-35 in pre-gestational activity
Progestational drug equivalent to about 150 μg, and daily dose range of about 10 to about 35 μg
21 days of a daily dose unit of ethinyl estradiol in 21 days; b) a second day of a daily dose unit of 3 days of the antiprogestin of claim 1 administered in a daily dose of about 2 to 50 mg; ) A pharmaceutically useful kit adapted for daily oral administration according to claim 16 comprising: 4 daily dose units of an orally and pharmaceutically acceptable placebo for 4 days. 18. A) a pre-pregnant drug in a daily dose, wherein each daily dose unit is equal to about 35 to about 150 μg levonorgestrel in pre-pregnant activity, and ethinyl estradiol in a daily dose range of about 10 to about 35 μg. 18-18 days of daily dosage unit containing 1st phase; b) each daily dosage unit contains the antiprogestin of claim 1 at a concentration of 2 to 50 mg, and ethinyl estradiol at a concentration of about 10 to about 35 μg. , A daily dosage unit of 1 to 7 days of the second phase; and c) an oral and pharmaceutically acceptable placebo daily dosage unit of the 0th to 9th day of the third phase: A pharmaceutically useful kit adapted for daily oral administration, wherein the total number of daily dose units in phases 2 and 3 is equal to 28. 19. A) containing the pre-pregnant drug of the present invention in a daily dose equal to about 35 to about 150 μg levonorgestrel in pre-gestational activity, and ethinyl estradiol in a daily dose range of about 10 to about 35 μg. 21 days of daily dosage units for the first phase; b) each daily dosage unit containing the antiprogestin of claim 1 at a concentration of 2 to 50 mg and ethinyl estradiol at a concentration of about 10 to about 35 μg. 19. A daily oral administration according to claim 18, comprising: 3 days of dosage unit of the second phase; and c) Orally and pharmaceutically acceptable placebo of the third day of 4 days of the dosage unit. Adapted pharmaceutically useful kit.